Biology subjects

Karve, S.

Publications and source records attributed to Karve, S..

4 recordsLinked to original sources

bioRxiv2026

Divergent genotype-phenotype maps determine the capacity for adaptation to antibiotics among Enterobacteria

What dictates the extent to which a bacterial strain can evolve under antibiotic pressure remains poorly defined, despite its implications for the effectiveness of antibiotics in clinical practice. In this study, we compare the evolution of Escherichia coli and Klebsiella aerogenes, two medically relevant members of Enterobacteriaceae, under colistin and trimethoprim selection. We discover that the mere presence of effector genes of resistance, as well as conserved gene regulatory architecture, do not necessarily translate to similar evolvabilities during antibiotic challenge. Instead genotype-phenotype maps of adaptive mutations, which can diverge at different biological levels, govern how effectively a strain evolves resistance. Both, E. coli and K. aerogenes, demonstrated strikingly parallel capacities for adaptation to trimethoprim, as a result of conserved mechanisms of resistance, including drug target modification and efflux. On the other hand, E. coli was driven to extinction by colistin, while K. aerogenes was able to evolve a high level of colistin resistance. Like the better studied K. pneumoniae, K. aerogenes acquired mutations in the BasSR (also called PmrAB) and PhoQP two-component signalling pathways under colistin selection. These mutations increased the expression of chromosomally-encoded lipopolysaccharide (LPS) modifiers, EptA and Arn. Similar mutations in E. coli were unable to confer protection against colistin, despite successfully up-regulating homologous effectors genes. However, expression of MCR-1, a horizontally acquired EptA-homolog found in clinical strains, conferred high level colistin resistance to E. coli. This difference in the intrinsic capacity to adapt to colistin was reflected in frequencies of resistance among clinical isolates from around the world. It also altered the dependency of Escherichia and Klebsiella species on horizontal gene acquisition for colistin resistance. Our study highlights the importance of understanding pathogen-specific genotype-phenotype maps of drug resistance to better predict long-term effectiveness of antibiotic therapies and define resistance-proof treatment strategies.

microbiology↗

bioRxiv2023

Genomic sequencing should extend to diverse priority pathogens for effective study and surveillance of antimicrobial resistance: a systematic review of whole-genome sequencing studies from India

BackgroundAntimicrobial resistance (AMR) is a public health emergency in many low and middle-income countries, including India. To effectively tackle AMR, we need rapid diagnostics, effective surveillance and new antimicrobial drugs. Whole-genome sequencing of pathogens is the first definite step towards achieving these goals. MethodsIn this work, we review all the studies published till date that report whole-genome sequences of select priority AMR pathogens from India. We searched PubMed and Web of Science databases for the studies that involved whole-genome sequencing of AMR priority pathogens from India. For the top two highly sequenced pathogens, S. typhi and K. pneumoniae, we performed phylogenetic analyses to understand the geo-climatic distribution of genetically diverse strains. ResultsOur search reveals 94 studies that report 2547 unique whole-genome sequences. We find that most sequences are limited to select priority pathogens isolated from a couple of geo-climatic zones of India. Our phylogenetic analyses show that available data does not indicate systematic differences between the genomes of isolates from different geo-climatic zones. Our search also reveals complete absence of travel-related studies tracking possible movement of AMR pathogens within country. Lastly, we find very few studies that sequence AMR pathogens isolated from food, soil or other environments. ConclusionTogether, these observations suggest that lndia should prioritize sequencing of diverse AMR pathogens from clinics as well as from environments and travellers rather than extending the geo-climatic range of already-sequenced pathogens. Our recommendations can be potentially valuable for other low and middle-income countries with limited resources, high prevalence of AMR and diverse geo-climatic conditions.

microbiology↗

bioRxiv2020

Immunogenicity of novel mRNA COVID-19 vaccine MRT5500 in mice and non-human primates

An effective vaccine to address the global pandemic of coronavirus disease 2019 (COVID-19) is an urgent public health priority1. Novel synthetic mRNA and vector-based vaccine technologies offer an expeditious development path alternative to traditional vaccine approaches. Here we describe the efforts to utilize an mRNA platform for rational design and evaluations of mRNA vaccine candidates based on Spike (S) glycoprotein of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus causing COVID-19. Several mRNA constructs expressing various structural conformations of S-protein, including wild type (WT), a pre-fusion stabilized mutant (2P), a furin cleavage-site mutant (GSAS) and a double mutant form (2P/GSAS), were tested in a preclinical animal model for their capacity to elicit neutralizing antibodies (nAbs). The lead 2P/GSAS candidate was further assessed in dose-ranging studies in mice and Cynomolgus macaques. The selected 2P/GSAS vaccine formulation, now designated MRT5500, elicited potent nAbs as measured in two types of neutralization assays. In addition, MRT5500 elicited TH1-biased responses in both mouse and non-human primate species, a result that helps to address a hypothetical concern regarding potential vaccine-associated enhanced respiratory diseases associated with TH2-biased responses. These data position MRT5500 as a viable vaccine candidate for clinical development against COVID-19.

immunology↗

bioRxiv2019

Adapting in larger numbers can increase the vulnerability of Escherichia coli populations to environmental changes

Larger populations generally adapt faster to their existing environment. However, it is unknown if the population size experienced during evolution influences the ability to face sudden environmental changes. To investigate this issue, we subjected replicate Escherichia coli populations of different sizes to experimental evolution in an environment containing a cocktail of three antibiotics. In this environment, the ability to actively efflux molecules outside the cell is expected to be a major fitness-affecting trait. We found that all the populations eventually reached similar fitness in the antibiotic cocktail despite adapting at different speeds, with the larger populations adapting faster. Surprisingly, whereas efflux activity enhanced in the smaller populations, it decayed in the larger ones. The evolution of efflux activity was largely shaped by pleiotropic responses to selection and not by drift. This demonstrates that quantitative differences in population size can lead to qualitative differences (decay/enhancement) in the fate of a character during adaptation to identical environments. Furthermore, the larger populations showed inferior fitness upon sudden exposure to several alternative stressful environments. These observations provide a novel link between population size and vulnerability to environmental changes. Counter-intuitively, adapting in larger numbers can render bacterial populations more vulnerable to abrupt environmental changes.

evolutionary biology↗